Molecular mechanism and physiological function of mitochondrial calcium regulation

线粒体钙调节的分子机制及生理功能

• 批准号: 10192800
• 负责人: Julia Chang Liu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192800
• 关键词: Academia; Address; Advisory Committees; Aging; Alleles; Alzheimer' s disease model; Animal Model; Animals; Architecture; Ataxia; Award; Biochemical Genetics; Bioenergetics; Bioinformatics; Biology; Calcium; Cell Death; Cell Line; Cell physiology; Cells; Clinical; Collaborations; Communication; Complex; Computer Analysis; Core Facility; Cultured Cells; Data; Defect; Development Plans; Disease; Disease Progression; Embryonic Development; Ensure; Environment; Exhibits; Fellowship; Gatekeeping; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Homeostasis; Human; In Vitro; Job Application; Knock-out; Lead; Learning; Longevity; Mass Spectrum Analysis; Mediating; Mediation; Membrane Proteins; Memory; Mentors; Mentorship; Metabolism; Methods; Mitochondria; Modeling; Molecular; Morphology; Multiprotein Complexes; Mus; Muscle; Muscle Weakness; Muscular Dystrophies; Mutation; Myopathy; National Heart, Lung, and Blood Institute; Neurodegenerative Disorders; Neurologic Dysfunctions; Oral; Pathology; Patients; Perinatal mortality demographics; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Precipitation; Production; Professional Competence; Proteins; Proteomics; Publications; Reagent; Regulation; Reperfusion Injury; Reporting; Research; Rest; Role; Scientist; Secure; Signal Pathway; Signal Transduction; Stress; Symptoms; Techniques; Testing; Therapeutic; Tissues; Training; Work; age related; aged; calcium uniporter; career development; design; experience; gel electrophoresis; genetic approach; in vivo; knock-down; loss of function; mitochondrial permeability transition pore; mouse model; muscle strength; mutant; nervous system disorder; normal aging; novel; reconstitution; scaffold; skills; stem cell homeostasis; symptomatic improvement; tenure track; transcriptome; transcriptome sequencing; uptake

Project Summary/Abstract The candidate for this award seeks further mentored research experience while developing career skills to facilitate a successful transition to research independence. Therefore, she has proposed additional experimental and professional training during her postdoctoral fellowship in the lab of Dr. Toren Finkel at the NHLBI. She will take advantage of the outstanding scientific environment in her mentor's lab and at the NHLBI to learn new techniques, including proteomics, RNA sequencing, bioinformatics and computational analysis, and animal work including advanced phenotyping tests. To train her in these methods and assist her in her research aims, she has established collaborations with Dr. Elizabeth Murphy's lab and several NHLBI core facilities. Furthermore, the candidate has designed a career development plan to ensure she prepares thoroughly for an academic position by cultivating her oral and written communication, mentorship, and lab management skills. The candidate has assembled an advisory committee consisting of her primary mentor and several other scientists who not only have extensive scientific experience in fields related to the mitochondrial biology proposed in this grant, but also have committed to guiding her on presentations, job applications, and negotiation strategies. This training will help the candidate secure a tenure-track position in academia. The research goal of this proposal is to dissect the molecular mechanism and physiological role of mitochondrial calcium regulation. Mitochondrial uptake of calcium can help to stimulate ATP production, but too much calcium can lead to opening of the mitochondrial permeability transition pore, triggering cell death. The selective channel through which calcium can rapidly enter the mitochondria, the mitochondrial calcium uniporter, is a multi-protein complex whose components are beginning to be identified. EMRE and MICU1 are two of these proteins that in cell lines have been shown to play critical roles in regulation of calcium uptake. The candidate has generated the first mouse models of EMRE and MICU1 deletion to elucidate the in vivo role of mitochondrial calcium. Her recent publication showed that MICU1 deletion leads to mitochondrial calcium overload, leading to drastically decreased survival and other defects. She will next characterize the effect of EMRE deletion on the molecular architecture of the uniporter as well as on organismal physiology (Aim 1). Her preliminary data suggest that without EMRE, mitochondria cannot uptake calcium. Therefore, the candidate will use MICU1 and EMRE deletion as genetic reagents representing “gain” and “loss” of function in terms of mitochondrial calcium uptake to elucidate how mitochondrial calcium regulation alters in vivo physiological function in global gene expression, aging, and disease (Aim 2). A number of muscular and neurodegenerative diseases have long been associated with mitochondrial calcium overload, but the generation of these mouse models will enable the first direct tests of the impact of mitochondrial calcium on organismal physiology. The completion of these aims thus is of both basic and clinical importance.

项目总结/摘要 该奖项的候选人寻求进一步的指导研究经验，同时发展职业技能， 促进向研究独立性的成功过渡。因此，她建议增加 在她的博士后研究期间，她在托伦·芬克尔博士的实验室接受了实验和专业培训。 NHLBI。她将利用她导师的实验室和NHLBI出色的科学环境 学习新技术，包括蛋白质组学，RNA测序，生物信息学和计算分析， 和动物实验，包括先进的表型测试。在这些方法上训练她， 研究目标，她已经建立了与伊丽莎白墨菲博士的实验室和几个NHLBI核心合作 设施此外，候选人已经设计了一个职业发展计划，以确保她准备 通过培养她的口头和书面沟通，指导和实验室，彻底的学术地位 管理能力候选人已经组建了一个咨询委员会，由她的主要导师组成， 其他几位科学家不仅在线粒体相关领域拥有丰富的科学经验， 生物学提出了这项补助金，但也致力于指导她的演讲，工作申请， 谈判策略。这项培训将帮助候选人在学术界获得终身职位。 本提案的研究目标是剖析 线粒体钙调节线粒体对钙的吸收有助于刺激ATP的产生，但也 过多的钙可导致线粒体通透性转换孔的开放，从而引发细胞死亡。的 选择性通道，通过它钙可以迅速进入线粒体，线粒体钙 单向转运蛋白是一种多蛋白质复合物，其成分已开始被识别。EMRE和MICU 1是 这些蛋白质中的两种在细胞系中已显示在钙摄取的调节中起关键作用。 候选人已经产生了EMRE和MICU 1缺失的第一个小鼠模型，以阐明体内作用 线粒体钙离子。她最近的出版物表明，MICU 1缺失导致线粒体钙 过载，导致生存率急剧下降和其他缺陷。她接下来将描述 EMRE缺失对单向转运蛋白的分子结构以及生物体生理学的影响（目的1）。她 初步数据表明，没有EMRE，线粒体不能摄取钙。因此，候选人将 使用MICU 1和EMRE缺失作为基因试剂，代表功能的“获得”和“丧失”， 线粒体钙摄取，以阐明线粒体钙调节如何改变体内生理 在全球基因表达，衰老和疾病中的作用（目的2）。一些肌肉和神经退化 长期以来，疾病与线粒体钙超载有关，但这些小鼠的产生 这些模型将首次直接测试线粒体钙对生物生理学的影响。的 因此，实现这些目标具有基本和临床重要性。